Context

Despite decades of focused research, treatments for neurology-related disorders are limited. However, recent work promises to widen the window on options. Several avenues of investigation have raised hopes that research will finally begin to cross the chasm between bench and bedside by developing treatments for the millions of people afflicted by debilitating disorders like Parkinson's, Huntington's, ALS and stroke.

In the offing in 2017 is a multiplicity of breakthroughs, including the first Food and Drug Administration approved drug to treat spinal muscular atrophy, a rare hereditary disease that impairs movement and is the most common genetic cause of infant death. At least seven other studies will be producing data in the next 18 months and two pharma powerhouses, Biogen and Celgene, are competing over multiple sclerosis treatments. Meanwhile, researchers are questioning the very theories behind how neurological disorders originate and progress.

Innovations are also happening in the technology used for research. The same is true for neurology clinical trials, which are moving toward analyzing neurological disorders according to specific symptoms and individualized molecular features rather than to take a “one size fits all” approach toward all patients with a phenotypically similar disease. This emphasis is driven in part by programs like the Precision Medicine Initiative. Likewise, an emphasis on interdisciplinary collaborations will be driven by implementation of the 21st Century Cures Act, which will begin to be felt in 2017. The $6.3 billion bill encourages research into regenerative medicine therapies for otherwise incurable conditions, including brain disorders. The goal is to get them to market more quickly, without sacrificing patient safety.

How these projections play out in neurology clinical trials over the course of 2017 remain to be seen. Much depends on the Trump administration, the 115th Congress and new leadership in key agencies. One thing is certain, though: The coming months promise to bring an impetus for change, collaboration and innovation.

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Change, Collaboration and Innovation: Trends in Neurology Clinical Trials 2017

KEY POINTS Pipeline: new therapies are now being marketed or are in late-stage trials Technology: The gene-editing technique CRISPR is breaking through to neurology trials Tele-Trials: The FDA is exploring novel approaches to clinical trial monitoring Public-Private: The government will increasingly invite industry collaborations Transparency: Data is driving pressure to show rigor and reproducibility in studies Regulatory: The industry is watching new leadership in key agencies, user fees and stem cell regulations Next Steps: Innovative trial design and a strong push for interdisciplinary collaboration joins traditional trial designs

Pipeline

Industry partners and patients are eagerly waiting for results from a number of potentially breakthrough neurology clinical trials currently underway and that will be reported between now and mid-2018. A few of the highlights include:

Spinraza In December 2016, the FDA approved Spinraza (nusinersen), the first drug to treat children and adults with spinal muscular atrophy. Spinraza is an antisense oligonucleotide which increases production of survival motor neuron 2 (SMN2), a protein which results in preservation of motor neurons and muscular function. The FDA gave the application fast track status, priority review and designated Spinraza as an orphan drug, in addition to granting a pediatric disease priority review voucher. The question remains whether long-term toxicity will pose a problem, and whether Spinraza, marketed by Biogen, will continue to be effective over time. Data from these trials will help researchers understand the promise of the technique for other neurological disorders.

Ocrevus and Ibudilast The U.S. Food and Drug Administration also fast-tracked approval of Genentech’s Ocrevus (ocrelizumab), which treats certain forms of multiple sclerosis, including primary progressive multiple sclerosis (PPMS). Ocrevus is a humanized anti-CD4 monoclonal antibody targeting the immune system. Ocrevus marks the first drug approved by the FDA for PPMS, a common form of the autoimmune disease that affects about 15 percent of patients with the disorder. In addition, results are expected from the Phase II SPRINT-MS biomarker trial of ibudilast (MN-166), an experimental oral phosphodiesterase inhibitor with anti-inflammatory properties. MediciNova is running the trial in collaboration with the National Institutes of Health, National Institute of Neurological Disorders and Stroke and the National Multiple Sclerosis Society.

Crenezumab Roche’s Genentech is starting a second Phase III clinical trial of the Alzheimer’s immunotherapy treatment, crenezumab. Crenezumab is a humanized monoclonal antibody directed against a toxic beta-amyloid protein fragment found in the brains of people with Alzheimer's disease. The trial complements a current Phase III trial, called CREAD1, which will begin producing data in 2020. Although results in the past were disappointing, the new trial, CREAD2, is hoping to improve treatment outcomes by increasing the dosage by four times.

Axovant Axovant, a clinical-stage pharmaceutical company, will produce data from at least five different advanced phase clinical trials in 2017 for Alzheimer's disease and Lewy Body Dementia treatments. One of them is a large international Phase III study, MINDSET, to evaluate intepirdine (RVT-101), a selective 5-HT6 receptor antagonist, in patients with mild-to-moderate Alzheimer’s disease. If approved, this will be the first new Alzheimer’s drug on the market in 17 years.

Stem Cells Recent breakthroughs using adult mesenchymal stem cells has prompted claims that neurological research is at a turning point, ready to finally make the leap from animal studies into late-stage trials and eventually real-world use: "Cell-based therapies are at the cutting edge of experimental stroke treatment, currently being translated in early stage clinical studies." These treatments offer the possibility of repairing what was previously considered irreversible damage. Hopes are also high for other disorders such as ALS, Parkinson's and Huntington's disease.

NeurovascularAnother avenue of investigation into neurological disorders takes advantage of the links between the brain and the heart. This line of neurovascular inquiry attempts to unite research into cardiac arrest and stroke, for example, two diseases that are leading causes of death in the United States but have been treated separately even though evidence has shown that vascular disease (e.g. high blood pressure, diabetes, obesity) is closely related to dementia. Current advances offer the "potential to overcome almost two decades of marginally successful translational research on stroke and dementia, thereby spurring the entire field of translational neuroscience."

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Technology

The gene-editing technique CRISPR broke through in 2017, when a team at Sichuan University in Chengdu inserted the cells modified (or, "edited") using the CRISPR-Cas9 enzyme into a patient with aggressive lung cancer as part of a clinical trial. Now the technology is being used to find new screening tools for Parkinson’s disease. Researchers at the University of Florida have used CRISPR to insert the gene for luciferin/luciferase (a luminescent tag made from prot that gives fireflies their glow) into neuons. The bioluminescence measures the brain protein alpha-synuclein, abnormal levels of which are associated with Parkinson’s. This work will help to identify effective treatments and, in the future, prevention of the disease.

Tele-Trials Instead of asking elderly, sick or incapacitated participants to travel to clinical trial sites, sometimes hundreds of miles away from home, the FDA is exploring novel approaches to clinical trials such as remote monitoring, commonly known as telemedicine. Supporters claim that virtual strategies can also help lower costs associated with trials by detecting meaningful signals earlier in the development of a new treatment, thus preventing unnecessary and expensive failures in Phase III. To be competitive in this climate, clinical trial teams need to equip themselves with the technology and legal framework involved in remote monitoring, such as having the appropriate videoconferencing setup, and personnel comfortable with apps and devices.

Public-Private The government will increasingly invite industry collaborations such as the Medical Device Innovation Consortium, a public–private partnership among industry, nonprofit organizations and the FDA to explore ways to use computer modeling and simulation in clinical trials. Likewise, at the NIH, the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative offers neurological research funding to collaborative efforts, including those with industry. The NIH initiative plans to spend $195 million in 2017 on projects that address fundamental neuroscience questions and advanced understanding of the human brain, including devices for mapping and tuning brain circuitry. By accelerating the development and application of innovative technologies, the NIH hopes to decode interactions in individual cells and complex neural circuits and, ultimately, unlock the mystery of our senses, memory, emotion and thought.

Transparency Scientists are increasingly expected not only to publish their results and to make available raw data and computer code so that studies can be tested. Indeed, NIH applicants are seeing their research proposals judged by transparency in addition to scientific rigor, to help explain results which t seem successful initially but prove disappointing when repeated. It is a concern clinical trial communities began addressing decades ago. Part of the blame today is attributed to an overemphasis on publications in clinical research. Journal articles that show positive results play a significant role in determining grant funding, leading to "publication bias." Publications with contradictory results have led one team of stroke researchers to note that: "Conclusions drawn from individual publications or from narrative reviews cannot provide the basis for selecting drugs for clinical trial or for the design of those clinical trials."

Regulatory President Donald Trump chose Scott Gottlieb, a 44-year old physician, to serve as commissioner of the Food and Drug Administration, which oversees the safety of the pharmaceutical system on behalf of consumers. Although Gottlieb's most pressing priority appears to be reducing the scope of opioid addiction in the United States, one of his most controversial suggestions would put final FDA approval in the hands of political appointees instead of career staff. Congress also confirmed Trump’s choice of former U.S. Rep. Tom Price to lead the Department of Health and Human Services, which directly oversees the NIH. Price strictly opposes embryonic stem cell research and would likely keep the federal moratorium on related research in place, as well as roll back policies and exemptions loosened under the administration of Barack Obama. This may add new incentive to efforts aimed at countering hurdles. Advocates have, for example, proposed a consortium to improve the public understanding of the scientific, as well as the social, legal and moral issues, involved in stem cell-based therapies.

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User Fees Both the FDA and NIH will have to prepare for budget cuts. These cuts should be softened by user fees paid by manufacturers of drugs, devices and other medical products, as well as the Cures Act. However, a fight over user fees may erupt. Under his spending blueprint released in May, Trump would double these fees. Congress, which controls the federal purse strings, is expected to oppose the increase in its own budget, scheduled to arrive on the president's desk by the new start of the new fiscal year, Oct. 1, 2017.

Next Steps Randomized, double blind studies will remain the gold standard. According to one team, “the best clinical trial design available to demonstrate disease-modification is a long-term follow-up study, in which an examination is made for sustained divergence in outcome measures between treatment arms over the study period.” Still, changes on the horizon in 2017 could affect the future of clinical trial requirements by transitioning from the classical approach of large, longitudinal studies toward innovative adaptive and other alternative designs. Driven by cultural and technological -- as much as financial and regulatory -- trends, trials will target specific genetic groups rather than diseases per se and success will require that trials work for both patients and sponsors. Clinical trials can help usher in new therapeutic avenues that promise to revolutionize neurological treatment. This optimism must be tempered by the fact that expedited FDA review has yet to have an impact on neurology clinical trials (a representative Biomedtracker analysis of clinical drug development success rates found that between 2006 to 2015, Phase II clinical programs continued to experience the lowest success rate of the four development phases, with only 31 percent of developmental candidates advancing to Phase III). Seen from another perspective, this history of challenge serves to emphasize the need for interdisciplinary collaboration to find novel ideas and collaborative concepts to bypass roadblocks.

1 Boltze, Johannes, and Cenk Ayata. “Challenges and Controversies in Translational Stroke Research - an Introduction.” Translational Stroke Research 7, no. 5 (October 1, 2016): 355–57. doi:10.1007/s12975-016-0492-4.

2 Demuth, Hans-Ulrich, at al. “Recent Progress in Translational Research on Neurovascular and Neurodegenerative Disorders.” Restor Neurol Neurosci 35, no. 1 (n.d.): 87–103.

3 Sena, Emily, H. Bart van der Worp, David Howells, and Malcolm Macleod. “How Can We Improve the Pre-Clinical Development of Drugs for Stroke?” Trends in Neurosciences 30, no. 9 (September 2007): 433–39. doi:10.1016/j.tins.2007.06.009.

4 McGhee, David J. M., Craig W. Ritchie, John P. Zajicek, and Carl E. Counsell. “A Review of Clinical Trial Designs Used to Detect a Disease-Modifying Effect of Drug Therapy in Alzheimer’s Disease and Parkinson’s Disease.” BMC Neurology 16 (June 16, 2016). doi: 10.1186/s12883-016-0606-3.

5 Maron, Dina Fine. “Here’s What We Know about Trump’s FDA Head Nominee.” Scientific American. Accessed May 29, 2017. https://www.scientificamerican.com/article/heres-what-we-know-about-trumps-fda-head-nominee/.

6 “Clinical Development Success Rates 2006-2015.” BIO, 2016. http://bit.ly/2sj2jFg

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